Hearing loss affects over 40 million people in the United States. It is the most common form of sensory defect in humans. The mechanism of hearing is still largely unknown despite recent advances in molecular medicine. The goal of this proposal is to apply two molecular biology techniques, genomic mismatch scanning and DNA microarray, to gain a better understanding of the genetic basis of hearing loss. This will eventually affect the prevention, treatment and care of hearing disorders. Genomic mismatch scanning (GMS) is a high-throughput genetic linkage technique that allows physical isolation of the identical-by-descent DNA fragments shared between two related individuals. In this proposal, we plan to apply GMS to confirm the localization for DFNBI, the gene for non-syndromic autosomal recessive deafness that has been mapped by linkage to chromosome 13q. Then, we will narrow the DFNBI candidate region using linkage disequilibrium mapping. This has been difficult with traditional mapping strategies due to the need for a very dense set of polymorphic markers. However, in GMS, a dense set of completely informative markers is scanned simultaneously on a whole genome level. In addition, during the grant period, we will develop a DNA microarray that will allow mapping of the identical-by-descent DNA fragments isolated by GMS on a whole genome level in one hybridization step. This DNA microarray will allow mapping of other deafness loci with unknown genomic locations. Finally, we will develop a linkage analysis model for the identity-by-descent maps generated by GMS. Upon achieving the goals delineated in this proposal, we hope to have contributed to the understanding of the genetic control of hearing and have provided a robust method that is a promising tool for the next generation of gene mapping.